Current Drug Discovery Technologies - Volume 18, Issue 3, 2021

Alcoholic and non-alcoholic fatty liver diseases have become a serious concern worldwide. Both these liver diseases have an identical pathology, starting from simple steatosis to cirrhosis and, ultimately to hepatocellular carcinoma. Treatment options for alcoholic liver disease (ALD) are still the same as they were 50 years ago which include corticosteroids, pentoxifylline, antioxidants, nutritional support and abstinence; and for non-alcoholic fatty liver disease (NAFLD), weight loss, insulin sensitizers, lipid-lowering agents and anti-oxidants are the only treatment options. Despite broad research in understanding the disease pathophysiology, limited treatments are available for clinical use. Some therapeutic strategies based on targeting a specific molecule have been developed to lessen the consequences of disease and are under clinical investigation. Therefore, focus on multiple molecular targets will help develop an efficient therapeutic strategy. This review comprises a brief overview of the pathogenesis of ALD and NAFLD; recent molecular drug targets explored for ALD and NAFLD that may prove to be effective for multiple therapeutic regimens and also the clinical status of these promising drug targets for liver diseases.

Most of the clinical approved protein-based drugs or under clinical trials have a profound impact on the treatment of critical diseases. The mammalian eukaryotic cells culture approaches, particularly the CHO (Chinese Hamster Ovary) cells are mainly used in the biopharmaceutical industry for the mass-production of the therapeutic protein. Recent advances in CHO cell bioprocessing to yield recombinant proteins and monoclonal antibodies have enabled the expression of quality protein. The developments of cell lines are possible to enhance specific productivity. As a result, it holds an interesting area for academic as well as industrial researchers around the world. This review will focus on the recent progress of the mammalian CHO cells culture technology and the future scope of further development for the mass-production of protein therapeutics.

Diseases are often caused by mutant proteins. Many drugs have limited effectiveness and/or toxic side effects because of a failure to selectively target the disease-causing mutant variant, rather than the functional wild type protein. Otherwise, the drugs may even target different proteins with similar structural features. Designing drugs that successfully target mutant proteins selectively represents a major challenge. Decades of cancer research have led to an abundance of potential therapeutic targets, often touted to be “master regulators”. For many of these proteins, there are no FDA-approved drugs available; for others, off-target effects result in dose-limiting toxicity. Cancer-related proteins are an excellent medium to carry the story of mutant-specific targeting, as the disease is both initiated and sustained by mutant proteins; furthermore, current chemotherapies generally fail at adequate selective distinction. This review discusses some of the challenges associated with selective targeting from a structural biology perspective, as well as some of the developments in algorithm approach and computational workflow that can be applied to address those issues. One of the most widely researched proteins in cancer biology is p53, a tumor suppressor. Here, p53 is discussed as a specific example of a challenging target, with contemporary drugs and methodologies used as examples of burgeoning successes. The oncogene KRAS, which has been described as “undruggable”, is another extensively investigated protein in cancer biology. This review also examines KRAS to exemplify progress made towards selective targeting of diseasecausing mutant proteins. Finally, possible future directions relevant to the topic are discussed.

Curcumin is one of the important natural compounds that is extracted from turmeric. This compound and its derivatives have numerous biological properties, including antioxidant, anticancer, anti-inflammatory, antimicrobial, and healing effects. Extensive research in various fields has been conducted on turmeric as it is widely used as a food additive. The significant antifungal activity is one of the major effects of curcumin. In this paper, recent studies on the effects of different forms of curcumin drug on the candidiasis were systematically examined and discussed. The data in this study were extracted from the articles and reports published in the Web of Science, Google Scholar, PubMed, and Scopus databases. After the preliminary investigation, relevant reports were selected and classified based on the incorporated formulation and purpose of the study. After a systematic discussion of the data, it was found that the use of medicinal forms based on nanoparticles can increase the absorption and target the controlled release of curcumin with a more effective role compared to other formulations. Consequently, it can be concluded that new methods of modern medicine can be employed to increase the efficacy of natural pharmaceutical compounds used in the past. In this regard, the present study analyzed the effect of curcumin against various Candida infections, using the recent data. It was found that applying a combination of drug formulation or the formulation of curcumin and its derivatives can be an effective strategy to overcome the medicine resistance in fungal infections, especially candidiasis.

Background: Antibiotic-resistant members of the family Enterobacteriaceae are among the serious threats to human health globally. This study reports the anti-pathogenic activity of Punica granatum peel extract (PGPE) against a multi-drug resistant, beta-lactamase producing member of this family i.e. Serratia marcescens. Objective: This study aimed at assessing the anti-pathogenic activity of PGPE against the gramnegative bacterial pathogen S. marcescens and identifying the molecular targets of this extract in the test bacterium. Methods: Effect of PGPE on S. marcescens growth and quorum sensing (QS)-regulated pigment production was assessed through broth dilution assay. In vivo anti-infective and prophylactic activity of PGPE was assessed employing the nematode worm Caenorhabditis elegans as a model host. Differential gene expression in PGPE-exposed S. marcescens was studied through a whole transcriptome approach. Results: PGPE was able to modulate QS-regulated pigment production in S. marcescens without exerting any heavy growth-inhibitory effect at concentrations as low as ≥2.5 μg/mL. It could attenuate the virulence of the test bacterium towards the worm host by 22-42% (p≤0.01) at even lower concentrations (≥0.5 μg/mL). PGPE also exerted a post-extract effect on S. marcescens. This extract was found to offer prophylactic benefit too, to the host worm, as PGPE-pre-fed worms scored better (34-51%; p≤0.001) survival in face of subsequent bacterial attack. Differential gene expression analysis revealed that PGPE affected the expression of a total of 66 genes in S. marcescens by ≥1.5 fold. Conclusion: The anti-virulence effect of PGPE against S. marcescens is multifaceted, affecting stress-response machinery, efflux activity, iron homeostasis, and cellular energetics of this bacterium notably. Among the major molecular targets identified in this study are LPS export transporter permease (LptF), t-RNA pseudouridine synthase (TruB), etc.

Background: Diabetic nephropathy can lead to renal diseases; oxidative stress and mitochondrial dysfunction have critical roles in its development. Objectives: In this study, the effect of syringic acid (SYR), a natural phenolic acid, on diabetic nephropathy and mitochondrial biogenesis was examined. Methods: Diabetes was induced in rats by injecting streptozotocin. SYR (25, 50 and 100 mg/kg/day) was orally administered for 6 weeks. SYR effects on factors, such as antioxidant activities and mRNA expression level of mitochondrial biogenesis indexes, were evaluated. Results: In SYR-treated rats, blood glucose and ALP level were significantly reduced. SYR increased kidney GSH content in the diabetic group. Elevated renal catalase and superoxide dismutase activities in diabetic rats were restored to normal levels after treatment. SYR significantly reduced the renal TBARS level, which had increased in diabetic rats. This compound also significantly upregulated renal mRNA expression of PGC-1α and NRF-1, and increased mtDNA/nDNA ratio in diabetic rats. These values were reduced in the non-treated diabetic group. The results show improvement of histopathological damages of kidney in the SYR treated group in comparison with the diabetic group. Conclusion: According to the results, SYR alters renal antioxidant defense mechanisms. Also, it could be considered as a novel approach by targeting mitochondria in renal diabetic complications.

Aims: The aim of this letter is to explore the influence of adding hydrogen atoms to the crystallographic structures of HIV-1 protease complexes with a series of inhibitors on the performance of radial distribution function based descriptors recently introduced in chemoinformatic studies. Background: Quite recently the successful application of molecular descriptors based on a radial distribution function to correlate it with biologically interesting properties of a ligand – enzyme complex was demonstrated. Except its predictive power, the analysis of atoms with dominant contributions to the RDFs can be used to identify relevant atoms and interactions. Since original paper was published on dataset consisting of the X-ray structures of complexes without hydrogen atoms, we wonder weather addition of light atoms can provide us new piece of information. Objective: The primarily objective is to create the model correlating the RDF based descriptors and physicochemical properties of the HIV-1 protease complexes with inhibitors with hydrogen atoms. Then, we will compare the performance of new model with previous one, where the hydrogen atoms were discarded. Information about interactions between the enzyme and the inhibitors will be extracted from the analysis of the RDF. Methods: The radial distribution function descriptor weighted by the number of valence shell electrons has proven to be sensitive to the changes in the structure of the enzyme and enzyme-ligand complexes. For each structure in our data set, RDF will be calculated and using multiple linear regression method the mathematical model will be designed correlating RDF based descriptors and the physicochemical properties. Statistical analysis of the atom’s contribution to the total RDF will reveal relevant interactions. Results: The applicability of RDF based descriptor for the correlation with pKi and EC50 values is demonstrated, while simple models containing only two or three parameters are able to explain 78 and 86 % of the variance, respectively. The models with explicitly included hydrogens are of comparable quality with the previous models without hydrogens. The analysis of the atom’s dominant contributions highlighted the importance of the hydroxyl groups of the inhibitor near the Asp25 and Asp25’ residues when it is bounded to the protease. Conclusion: Models based on the RDF weighted by the number of valence shell electrons for correlating small number of molecular descriptors and physicocehmical properties for structures with and without hydrogens are of comparable quality and both can be used for identification of relevant functional groups and interactions. Other: Our approach can be integrated to the next generation virtual screening methods, because is fast, reliable with high predictability potential.

Background: Different parts of Psidium guajava are consumed as food and used for medicinal purposes around the world. Although studies have reported their antiproliferative effects via different biochemical mechanisms, their modulatory effects on epigenetic modification of DNA molecules via histone deacetylases (HDACs) are largely unknown. Objective: This study was carried out to investigate the histone deacetylase 6 (HDAC6) and histone deacetylase 10 (HDAC10) binding propensity of guava-derived compounds, using in silico methods, in other to identify compounds with HDAC inhibitory potentials. Methods: Fifty-nine guava-derived compounds and apicidin, a standard HDAC inhibitor, were docked with HDAC6 and HDAC10 using AutodockVina after modeling (SWISS-MODEL server) and validating (ERRAT and VERIFY-3D) the structure of HDAC10. Molecular interactions between the ligands and the HDACs were viewed with Discovery Studio Visualizer. Prediction of binding sites, surface structural pockets, active sites, area, shape and volume of every pocket and internal cavities of proteins was done using Computed Atlas of Surface Topography of proteins (CASTp) server, while absorption, distribution, metabolism, and excretion (ADME) study of notable compounds was done using Swiss online ADME web tool. Results: 2α-hydroxyursolic acid, asiatic acid, betulinic acid, crategolic acid, guajadial A and B, guavacoumaric acid, guavanoic acid, ilelatifol D, isoneriucoumaric acid, jacoumaric acid, oleanolic acid, psiguadial A, B, and C demonstrated maximum interaction with the selected HDACs. ADME studies revealed that although isoneriucoumaric and jacoumaric acid ranked very high as HDAC inhibitors, they both violated the Lipinski’s rule of 5. Conclusion: This study identified 13 drugable guava-derived compounds that can be enlisted for further studies as potential HDAC6 and HDAC10 inhibitors.

Background: Chikungunya fever is a challenging threat to human health in various parts of the world nowadays. Many attempts have been made for developing an effective drug against this viral disease and no effective antiviral treatment has been developed to control the spread of the Chikungunya virus (CHIKV) in humans. Objective: This research is aimed at the discovery of potential inhibitors against this virus by employing computational techniques to study the interactions between non-structural proteins of Chikungunya virus and phytochemicals from plants. Methods: Four non-structural proteins were docked with 2035 phytochemicals from various plants. The ligands having binding energies ≥ -8.0 kcal/mol were considered as potential inhibitors for these proteins. ADMET studies were also performed to analyze different pharmacological properties of these docked compounds and to further analyze the reactivity of these phytochemicals against CHIKV, DFT analysis was carried out based on HOMO and LUMO energies. Results: By analyzing the binding energies, Ki, ADMET properties and band energy gaps, it was observed that 13 phytochemicals passed all the criteria to be a potent inhibitor against CHIKV in humans. Conclusion: A total of 13 phytochemicals were identified as potent inhibiting candidates, which can be used against the Chikungunya virus.

Aims: To utilize in silico-based approach for investigating the ability of PEGylated rapamycin as a competitive inhibitor to Galectin-3 for curing various diseases or that may provide an attractive strategy for treatment of a wide variety of tumors. Background: Galectin-3 (Gal-3) signaling protein is a unique member of lectin family present at the cell surface, intracellularly in both the nucleus and cytoplasm and extracellularly in the general circulation. Circulating Gal-3 is present in both normal and cancer cells. High levels of circulating Gal-3 have been proven to be associated with inflammation and fibrosis in several acute and chronic conditions, which include neurological degeneration, inflammatory and immune responses, autoimmune diseases, diabetes, heart failure, atherosclerosis, response to infection, wound healing, liver, lung, and kidney disease. Gal-3 is known to regulate many biological activities including cell adhesion, angiogenesis, growth, apoptosis, migration, and metastasis. Rapamycin has been examined alone or in combination with other drugs for treatment of various cancers in clinical studies. Although it has shown promising therapeutic effects, its clinical development was interrupted by poor aqueous solubility and limited preferential distribution. To overcome these limitations, RA has been chemically modified to hydrophilic analogues, such as everolimus (EV). However, all these approaches can only partially increase the solubility, but has little effect on the blood distribution and pharmacokinetics. Therefore, it is necessary to explore other RA conjugates to improve aqueous solubility and tissue distribution profile. Recently we reported that RP-MPEG inhibits the growth of various cancer cell lines by acting on mammalian target of RP (mTOR) receptor site and it can be used for gastric cancer. Objective: To construct various molecular weight RP-MPEG by replacing MPEG chain in 40-O-(2- hydroxyethyl) position of the EV and analyze their binding affinity to Gal-3. Methods: The chemical structures of various molecular weight RP-MPEG were built using ChemSketch software. The molecular docking study was performed to find the best probable structure of RP-MPEG for competitive inhibition of the CRD, based on the interaction score. For that purpose, the 3D structures of RP and EV were obtained from NCBI PubChem compound database, where the structural protein-co-crystallized ligand complex of Gal-3 (TD2, as a native ligand) was retrieved from RCSB Protein Data Bank. All structures of the selected compounds, served as molecules for molecular modeling, were optimized through MOE.2014 software before docking. Hydrogen atoms and partial charges were added to the protein. Protein minimization was performed in gas solvation with the side chains, keeping it rigid and the ligand flexible. The selected site was isolated and minimized, followed by protonating the protein. The 3D ligands were minimized using MMFF94x with cutoffs of 10 to 12 Å. The hydrogens and charges were fixed, and the RMS gradient was set to 0.001 kcal/mol. The docking results were analyzed to identify and assess the binding affinity of these compounds to CRD using drug discovery software. Results: Our results indicated that RP-MPEG with MW 1178.51 g/mol has a logP value of 3.79 and has possessed the strongest binding affinity toward CRD of Gal-3 with a docking score of -6.87. Compared with TD2, there were additional close contacts for RP-MPEG (MW 1178.51 g/mol), coming from three hydrogen bonds with Asp148, Arg162, and Arg144 which suggest that this ligand is a strong competitive inhibitor among the other molecules for Gal-3. Conclusion: RP-MPEG with the MW 1178.51 g/mol could be a promising blocker for various biological action of Gal-3 includes profibrotic activity, modulation of immune responses and inflammatory responses to cancer that contributes to neoplastic transformation, angiogenesis and metastasis. Other: The 95% confidence intervals (CIs) of the binding affinity (according to their mean and standard errors) were estimated with 2.5 and 97.5 percentile as the lower and upper bounds.

Aim: The aim of this study was to evaluate the efficacy of honey-based ophthalmic drop in patients with foreign body induced corneal ulcer. Background: Honey is traditionally used for skin, mucosal and corneal ulcers. Its use is well studied in human skin and mucosal ulcers and animal model of corneal ulcer with promising effects. Methods: In this randomized clinical trial, 50 patients with foreign body induced corneal ulcer were allocated to receive 70% sterile honey-based ophthalmic formulation or 0.3% ophthalmic ciprofloxacin, as the standard treatment every 6 hours. All the patients were examined for the size of corneal epithelial defect, corneal infiltration and depth and followed on a daily basis until complete healing. Duration for complete healing was considered as the outcome measure. Smear, culture, antibiogram and minimum inhibition concentration (MIC) tests were performed for honey and ciprofloxacin in all patients. Results: The average durations of complete healing of corneal epithelial defect in the honey and ciprofloxacin groups were 3.88 ± 3.44 vs. 6.32 ± 3.69days, respectively (p=0.020). No significant difference was observed between two groups regarding an average duration of healing of corneal infiltration (8.12 ±1.94 days vs. 8.64±2.15 days, p=0.375). MIC of honey for pseudomonas aeruginosa was 60%w/w, for E.Coli 40% w/w, and for staphylococcus aureus 30% w/w. Conclusion: Honey based ophthalmic drop can acceleratethe corneal epithelial defect healing in patients with foreign body induced corneal ulcer, compared to ophthalmic ciprofloxacin as a standard treatment. The study was registered in Iranian registry of clinical trial center (IRCT) with registration number IRCT2015020120892N1.